One of the primary focus projects of our laboratory program centers on the eosinophil, an enigmatic leukocyte whose role in host defense remains a subject of significant controversy. Several lines of investigation from our laboratory have led us to consider the role of the eosinophil secretory ribonucleases (described further in Project Number AI000942-01), and by extension, the role of their primary host cells, the eosinophils, in host defense against a previously unrecognized group of target pathogens, specifically respiratory viruses of the family Paramyxoviridae (described further in Project Number AI000943-01). As part of our larger interest in eosinophils and their role in inflammation, we began with an extensive gene microarray study designed to explore the molecular basis of development and differentiation of mouse eosinophils in vivo. The results of this work were initially published in Blood (Bystrom et al. 2004). In a study published this year, we explored signal transduction and eosinophil colony expansion promoted by the cytokine, interleukin-5 (IL-5) via interactions with its heterodimeric receptor (IL-5R). Two variants encoding soluble forms of the alpha subunit (sIL-5Ralpha) have been described, although the signals promoting and/or limiting differential transcription of these soluble forms have not been clarified to any significant extent. Our intent was to explore the role of IL-5 in regulating differential transcription of these splice variants via a quantitative reverse transcriptase-PCR assay to detect transcripts encoding the transmembrane, soluble 1 and soluble 2 forms of IL-5Ralpha in two strains of wild type (BALB/c and C57BL/6) and corresponding IL-5 gene-deleted mice. Ultimately, we found that IL-5 was not necessary for differential splicing to occur in vivo, as all three forms of the IL-5Ralpha were detected in both strains of IL-5 gene-deleted mice, with ratios of transcript expression (transmembrane: soluble 1: soluble 2) that were indistinguishable from their wild type counterparts. Differential splicing did vary markedly between strains, however, potentially due to local effects of strain-specific polymorphisms. The results of this work have been accepted for publication (Bystrom et al. 2006. Eur. J. Haematol, In press.) We have also been fortunate to have access to both new mouse models of eosinophil ablation, known as ddblGATA and TgPHIL. With these lineage-ablated mice, we explored the controversial issue of the role of eosinophils in host defense against helminthic parasites using the established Schistosoma mansoni infection model. No eosinophils were detected in bone marrow of infected ddblGATA or TgPHIL mice, despite the fact that serum IL-5 levels in these infected mice exceeded those in infected wild type by ~ 4-fold. Liver granulomata were likewise depleted of eosinophils compared to those from their respective wild types. No eosinophil-dependent differences in granuloma number, size, or hepatic fibrosis were detected at weeks 8 or 12 of infection, and differential accumulation of mast cells was observed among the ddblGATA mice only at week 12. Likewise, serum levels of liver transaminases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increased in all mice in response to S. mansoni infection, with no eosinophil-dependent differences observed. Finally, eosinophil ablation had no effect on worm burden or on egg deposition. Overall, our data indicate that eosinophil ablation has no impact on traditional measures of disease in the S. mansoni infection model in mice. However, we cannot rule out the possibility that eosinophils may have unexplored immunomodulatory contributions to this disease process. The results of this work have likewise been accepted for publication (Swartz, Dyer et al., 2006. Blood, In press.) Finally, my expertise in eosinophil biology and inflammation has provided me with the opportunity to participate as a member of the Editorial Boards of Blood (since 2003), Journal of Leukocyte Biology (since 1996), Clinical and Vaccine Immunology (since 2003) and Faculty of 1000 Biology (since 2006). As a member of the Editorial Board of Blood, I have been given the opportunity to contribute several "Inside Blood" capsules profiling original publications (included in bibliography). Most recently, I have assisted in developing an original feature for the Journal of Leukocyte Biology known as "Pivotal Advance", and I have taken on the role of interviews editor. Four of these feature interviews have been published so far in 2006, and abstracted on PubMed (included in bibliography).